Hot melt extrusion processing parameters optimization

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The aim of this study was to demonstrate the impact of processing parameters of the hot-melt extrusion (HME) on the pharmaceutical formulation properties. Carbamazepine (CBZ) was selected as a model water-insoluble drug. It was incorporated into Soluplus®, which was used as the polymeric carrier, to produce a solid dispersion model system. The following HME-independent parameters were investigated at different levels: extrusion temperature, screw speed and screw configuration. Design of experiment (DOE) concept was applied to find the most significant factor with minimum numbers of experimental runs. A full two-level factorial design was applied to assess the main effects, parameter interactions and total error. The extrudates’ CBZ content and the in vitro dissolution rate were selected as response variables. Material properties, including melting point, glass transition, and thermal stability, and polymorphs changes were used to set the processing range. In addition, the extruder torque and pressure were used to find the simplest DOE model. Each change of the parameter showed a unique pattern of dissolution profile, indicating that processing parameters have an influence on formulation properties. A simple, novel and two-level factorial design was able to evaluate each parameter effect and find the optimized formulation. Screw configuration and extrusion temperature were the most affecting parameters in this study

Development and optimization of erythromycin-loaded lipid-based gel by Taguchi design: In vitro characterization and antimicrobial evaluation

The foremost aim of the current research was to prolong and sustain the release of erythromycin (ERY) by preparing a solid lipid nanoparticles (SLNs)-based gel formulation for the safe and effective treatment of acne. ERY-loaded SLNs were developed, and various process variables were optimized with respect to particle size, zeta potential, and entrapment efficiency using the Taguchi model. The average particle size, PDI, zeta potential, drug entrapment efficiency, and drug loading of optimized SLN (F4) were found to be 176.2±1.82 nm, 0.275±0.011, -34.0±0.84, 73.56%, and 69.74% respectively. The optimized SLN (F4) was successfully incorporated into the carbopol-based hydrogel. The in vitro release of ERY from the SLN gel and plain gel were compared and found to be 90.94% and 87.94% respectively. In vitro study of ERY-loaded SLN gel showed sustained delivery of drug from formulation thus enhancing the antimicrobial activity after 30 hours when compared to ERY plain gel

Characteristics and anticancer properties of Sunitinib malate-loaded poly-lactic-co-glycolic acid nanoparticles against human colon cancer HT-29 cells lines

Purpose: To develop poly-lactic-co-glycolic acid (PLGA) -based nanoparticles (NPs) for the delivery of sunitinib malate (STM) to colon cancer cells.Methods: Three different formulations (F1 – F3) were developed by nano-precipitation technique using various concentrations of PLGA. The NPs were evaluated for particle size, polydispersity index, zeta potential, drug entrapment, and drug loading, using differential scanning calorimetry (DSC), Fouriertransform infrared spectroscopy (FTIR), x-ray diffraction (XRD), and scanning electron microscopy (SEM). Furthermore, in vitro drug release and anticancer studies were carried out on the formulations.Results: Among the three NPs, optimized NP (F3) of STM was chosen for in vitro anti-cancer study against H-29 human colon cancer cells lines based on its particle size (132.9 nm), PDI (0.115), zeta potential (-38.12 mV), entrapment efficiency (52.42 %), drug loading (5.24 %), and drug release (91.26 % in 48 h). A significant anti-cancer activity of the optimized NPs was observed, relative to free STM.Conclusion: These findings suggest that STM-loaded NPs possess significant anti-cancer activity against human colon cancer HT-29 cells lines.Keywords: Sunitinib malate, Poly-lactic-co-glycolic acid, Nanoparticles, Colon cance

Hot Melt Extrusion Processing Parameters Optimization

The aim of this study was to demonstrate the impact of processing parameters of the hot-melt extrusion (HME) on the pharmaceutical formulation properties. Carbamazepine (CBZ) was selected as a model water-insoluble drug. It was incorporated into Soluplus®, which was used as the polymeric carrier, to produce a solid dispersion model system. The following HME-independent parameters were investigated at different levels: extrusion temperature, screw speed and screw configuration. Design of experiment (DOE) concept was applied to find the most significant factor with minimum numbers of experimental runs. A full two-level factorial design was applied to assess the main effects, parameter interactions and total error. The extrudates’ CBZ content and the in vitro dissolution rate were selected as response variables. Material properties, including melting point, glass transition, and thermal stability, and polymorphs changes were used to set the processing range. In addition, the extruder torque and pressure were used to find the simplest DOE model. Each change of the parameter showed a unique pattern of dissolution profile, indicating that processing parameters have an influence on formulation properties. A simple, novel and two-level factorial design was able to evaluate each parameter effect and find the optimized formulation. Screw configuration and extrusion temperature were the most affecting parameters in this study

Solubility enhancement, mechanical properties and taste masking of poorly water soluble compounds by optimizing hot melt extrusion processing

Pharmaceutical research includes investigation and development of a new drug and determination of the delivery route and delivery system, as well as the technology to create the delivery system. It can also consist of a combination of these steps. Researchers studying potential delivery routes have explored oral, nasal, dermal, transdermal, transmucosal, pulmonary, and injection routes for their ability to deliver large and small drug molecules. This research project focuses on the oral route, which is generally accepted as an effective delivery route for many drug products with a large market share, and studies the use of this route for the delivery of poorly soluble actives. Conventional delivery systems used for oral drug delivery are solid dosage forms including capsules filled with milled material, tablets, and pellets. Current research focusing on actives with low aqueous solubility requires new technology to obtain tailored drug release. This research project studies the use of hot melt extrusion (HME), together with hydrophilic polymers, to improve availability of poorly soluble compounds. In recent years HME has become widely accepted as a viable drug delivery system. HME is useful for several different purposes, including solid-state stability enhancement, taste masking, and solubility enhancement, and can be used in the production of a variety of drug dosage forms. The use of HME for solubility enhancement is the subject of this research. Solubility enhancement can be achieved by using HME to disperse a poorly soluble drug in a polymeric carrier matrix, forming a solid dispersion. This method can be used to form both amorphous and crystalline dispersions, but for solubility enhancement amorphous dispersions are used because of the free energy benefits associated with them. To create an amorphous solid dispersion, a drug polymer is melt-extruded then cooled at a rate that prevents recrystallization or processed at a temperature at which the melted drug is immiscible with the carrier. These processes result in kinetic entrapment of the compound in its amorphous state, produce the highest level of specific surface area, and increase saturation solubility, all of which work to improve drug solubility. These processes provide the benefit of increased dissolution rate because of higher thermodynamic activity, but the compounds still have the tendency to return to their crystalline forms. In order to realize the full potential of HME processes in improving drug delivery, it is necessary to have a comprehensive understanding of the physicochemical properties of the amorphous solid dispersions and their In vitro behavior. The most important application of HME technology in the pharmaceutical industry is for developing multi-particulate drug delivery systems. These are primarily oral dosage forms which consist of many, tiny, discrete units, each of which shows the desired characteristics. With multi-particulate systems the drug dosage is divided into multiple sub-units consisting of minute spherical particles with a diameter of 0.05-2.00 millimeters, or mini-tablets with diameters from 2.00-5.00 mm. The research project covered by this dissertation focuses on characterizing several hydrophilic polymeric extrudates produced through HME, and highlighting their various pharmaceutical applications. HME, when used together with an effective pelletizer, has been shown to be a practicable method for the development of novel mini-tablet and pellet dosage forms. Research concerning the use of HME for solubility enhancement focuses on producing amorphous solid dispersions using novel hydrophilic polymers and detailed description of the resulting melt-extrudates. It also studies the effects of different formulation variables and process parameters on the compounds produced. These lines of research aid in the development of modulated-drug-release, stable solid oral dosage form. The key objectives of the chapters in the dissertation are: (1) To Introduce Hot Melt Extrusion as prominent technique in pharmaceutical industry; (2) To prepare novel taste-masked mini-tablets of ketoprofen (KPR) with the taste-masking carrier Eudragit® E PO by HME and to evaluate the effectiveness of the taste masking with multiple in vitro methods. In addition, FTIR imaging was utilized to visually approximate drug homogeneity; (3) To formulate face-cut, melt extruded pellets and to optimize hot melt process parameters on pellets to obtain maximized sphericity and hardness utilizing Soluplus® as a polymeric carrier and carbamazepine (CBZ) as a model drug; (4) To assess the potential of Lutrol® F grades as polymeric surfactants for solubility enhancement of Kollidon®VA64 drug matrices produced by Hot Melt Extrusion

Design, statistical optimization, and characterization of Esculin-loaded transliposome nanogel for topical delivery: In-vitro, ex vivo study and dermatokinetic evaluation

The purpose of this study was to prepare and optimise an Esculin-loaded transliposome (ECL-TL) for the dermal administration of ECL for skin cancer treatment. The ECL-TL formulation effectively produced closed lamellar vesicles with in-vitro drug release of 81.28 ± 2.82 % and ex-vivo penetration studies showed that had a 2.2-part intensified permeability compared to the conventional preparation. The CLSM data of skin visibly displayed intense permeation of ECL-TL formulated with rhodamine B, equating to the rhodamine B hydroalcoholic solution. The dermatokinetic study suggested that TLs enhance the permeability of the delivery system when topically applied. According to the data, the developed ECL-TL could be an effective drug nano-carrier for the dermal delivery of ECL in treating skin cancer

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888

Effect of Lutrol\u3csup\u3e®\u3c/sup\u3e F grades (poloxamer) on dissolution of Hot-melt extruded Kollidon\u3csup\u3e®\u3c/sup\u3e VA64-felodipine matrices

The objective of this study was to assess the potential of Lutrol® F grades as polymeric surfactants for dissolution enhancement of Kollidon®VA64-drug matrices produced by hot-melt extrusion (HME). The poorly soluble model drug felodipine (FEL) with a medium melting point was selected for this study. Two different grades of Lutrol® F (also called Kolliphor® P grades) were added into the HME systems to investigate their influence on the drug-incorporated matrices. Two grades of Lutrols i.e., Lutrol® F 68 (Kolliphor®P 188) and Lutrol® F 127 (Kolliphor®P 407) were studied as polymeric solubilizers. FEL was mixed with Kollidon®VA64, with or without Lutrol®F (alone or in combination) at predetermined amounts which resulted in 8 different formulations. Each blend was melt-extruded at the same extrusion conditions. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses were performed to evaluate their physicochemical properties. DSC and PXRD studies suggested the formation of amorphous solid dispersion for all extruded formulations. Dissolution studies revealed that the extrudates with Lutrol® F grades exhibited faster and higher release compared to formulations without Lutrol® F grades. Formulations with high drug loading, which did not include Lutrol® F grades, demonstrated low drug release profiles when compared with the same formulations containing Lutrol® F grades. Fourier transform infrared (FTIR) studies suggested that a stronger hydrogen bond has occurred between the (-NH) of FEL and (C=O) of the pyrrolidone group in Kollidon® VA 64. Overall, these studies suggested the potential of Lutrols in enhancing the dissolution rate of poorly soluble model drug FEL

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888

Product Development Studies of Cranberry Seed Oil Nanoemulsion

Cranberry seed oil (CSO) can be used in various skin diseases, perhaps due to the presence of ω-3, ω-6, and ω-9 fatty acids. In addition, tocotrienols (vitamin E) has demonstrated powerful antioxidant activity. The combined application of CSO nanoemulsions open a promising avenue for skin conditions. The goal of this work was to create a nanoemulsion (NE) containing CSO and test its stability and in vitro release. To make NE formulations (CNE1-CNE6), the aqueous titration method was used. Following the creation of NE formulations, we selected the CNE4 formulation, which had a mean droplet size of around 110 nm, a narrow size distribution (PDI < 0.2), a steady zeta potential (−34.21 mV), and a high percentage transmittance (>99%). Furthermore, electron microscopy imaging revealed nanosized spherical droplets without any aggregation in the CNE4 formulation, which showed high entrapment efficiency (>80%). Densitometry analysis confirmed linoleic acid (RF 0.62) as a major component of CSO using toluene–acetone–glacial acetic acid (90:9:1 v/v/v) as a mobile phase. Nanogel had a three-fold greater cumulative drug permeation through the skin than neat CSO. This study shows that a unique CSO delivery technique can be used to treat skin diseases